Managing Chronic Tendon Pain by Metformin

Sponsor

James Wang (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06100822

Collaborator

United States Department of Defense (U.S. Fed)

Enrollment

Location

Arms

Anticipated Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the current exploratory clinical trial is to determine the effect of oral ingestion of metformin (OIM) in non-diabetic patients with chronic Achilles tendon pain. The trial has two aims; 1) to assess the effects of OIM treatment on tendon pain, and 2) to determine the effects of OIM capsules on tendon healing and repair. Twenty participants will be treated with metformin capsules for 16 weeks combined with a home exercise program. A comparison group of 20 participants will be treated with placebo tablets along with home exercise program.

Condition or Disease	Intervention/Treatment	Phase
Tendinopathy Chronic Pain Achilles Tendinopathy	Drug: Metformin Drug: Placebo	Phase 1

Detailed Description

This is a blinded and randomized controlled trial that focuses on the treatment effects of metformin (Met) on chronic tendon pain, healing, and repair in midportion Achilles tendinopathy. We will include a total 40 patients randomly divided into two equal groups:

Group 1: Home Exercise Program + Placebo as a control group

Group 2: Home Exercise Program + Oral Ingestion of Metformin

Patients in group 1 will receive placebo capsules,1 capsule (500 mg) daily for week one, 2 capsules (1,000 mg) daily for week two, 3 capsules daily for week 3 (1,500 mg), and 4 capsules daily (2,000 mg) for weeks 4-16. Patients in group 2 will receive metformin capsules,1 capsule (500 mg) daily for week one, 2 capsules (1,000 mg) daily for week two, 3 capsules daily for week 3 (1,500 mg), and 4 capsules daily (2,000 mg) for weeks 4-16. All patients will participate in a home exercise program through MedBridge, a HIPAA-compliant participant portal currently used by physical therapists at University of Pittsburgh Medical Center. There are 3 visits for this study. Visits include a Screening/Baseline visit, week 4 and week 16 visit. During each visit, participants will answer questions, complete functional testing, and undergo an ultrasound of the Achilles Tendon.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Managing Chronic Tendon Pain by Repurposing Metformin

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Feb 1, 2025

Anticipated Study Completion Date :

Apr 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Group, Placebo Capsules Placebo Group (n=20) Week 1: One placebo capsule (500 mg) daily Week 2: Two placebo capsules (1,000 mg) daily Week 3: Three placebo capsules (1,500 mg) daily Week 4-16: Four placebo capsules (2,000 mg) daily	Drug: Placebo 500 mg capsules of placebo pills
Experimental: Treatment Group, Metformin Capsules Treatment Group (n=20) Week 1: One metformin ER capsule (500 mg) daily Week 2: Two metformin (ER) capsules (1,000 mg) daily Week 3: Three metformin (ER) capsules (1,500 mg) daily Week 4-16: Four metformin (ER) capsules (2,000 mg) daily	Drug: Metformin 500 mg capsules of Metformin Extended Release Other Names: Glucophage Glucophage XR Metformin Extended Release Metformin ER

Arm

Intervention/Treatment

Placebo Comparator: Placebo Group, Placebo Capsules

Placebo Group (n=20) Week 1: One placebo capsule (500 mg) daily Week 2: Two placebo capsules (1,000 mg) daily Week 3: Three placebo capsules (1,500 mg) daily Week 4-16: Four placebo capsules (2,000 mg) daily

Drug: Placebo

500 mg capsules of placebo pills

Experimental: Treatment Group, Metformin Capsules

Treatment Group (n=20) Week 1: One metformin ER capsule (500 mg) daily Week 2: Two metformin (ER) capsules (1,000 mg) daily Week 3: Three metformin (ER) capsules (1,500 mg) daily Week 4-16: Four metformin (ER) capsules (2,000 mg) daily

Drug: Metformin

500 mg capsules of Metformin Extended Release

Other Names:

Glucophage

Glucophage XR

Metformin Extended Release

Metformin ER

Outcome Measures

Primary Outcome Measures

Change in Victorian Institute of Sport Assessment - Achilles (VISA-A) Score [baseline, 4 weeks, 16 weeks]
The VISA-A is a self-administered questionnaire that asks about Achilles tendon pain, function, and activity. Scores range from 0 to 100 with a low score indicating more severe pain.

Secondary Outcome Measures

Change in VAS score [baseline, 4 weeks, 16 weeks]
The VAS is a self-administered questionnaire that asks about pain. Scores range from 0 to 10 with a high score indicating more severe pain.
Change in tendon thickness [baseline, 4 weeks, 16 weeks]
Images of the Achilles tendon in long axis will be acquired using B-mode ultrasound imaging. Maximum Achilles tendon thickness (mm) will be measured by a blinded investigator.
Change in tendon cross-sectional area [baseline, 4 weeks, 16 weeks]
Images of the Achilles tendon in short axis will be acquired using B-mode ultrasound imaging. Maximum Achilles tendon cross-sectional area (mm^2) will be measured by a blinded investigator.
Change in tendon neovascularization [baseline, 4 weeks, 16 weeks]
Achilles tendon neovascularization will be evaluated using the 5-point modified Ohberg scale: 0 - no vessels visible one vessel, mostly anterior to the tendon one or two vessels throughout the tendon three vessels throughout the tendon more than three vessels throughout the tendon
Change in tendon hypoechogenicity [baseline, 4 weeks, 16 weeks]
Hypoechogenicity is indicative of disruption of the normal fibrillar structure of the Achilles tendon. Achilles tendon hypoechogenicity will be evaluated using a semi-quantitative 3-point scale: 0 - no hypoechogenicity - Heterogeneous echotexture with diffuse hypoechogenicity between fibrillar echoes and/or foci of discontinuity in collagen fibrillar echoes - Heterogeneous echotexture with discrete hypoechoic area/s of >1mm and/or presence of intrasubstance tears
Change in maximum number of heel raises [baseline, 4 weeks, 16 weeks]
The subject will stand barefoot on a 10° incline board and perform heel raises at a rate of 30 Hz (2 seconds per repetition, pace provided by audible metronome), while keeping their knee straight. Subjects will be allowed to have 2 fingertips per hand at shoulder height against the wall for balance. Participants will stop when they are unable to perform any additional repetitions, or if they fail to maintain proper form. Number of repetitions will be recorded.
Change in heel raise height [baseline, 4 weeks, 16 weeks]
The subject will stand barefoot on a 10° incline board and perform heel raises at a rate of 30 Hz (2 seconds per repetition, pace provided by audible metronome), while keeping their knee straight. Subjects will be allowed to have 2 fingertips per hand at shoulder height against the wall for balance. Participants will stop when they are unable to perform any additional repetitions, or if they fail to maintain proper form. Maximum height of heel rise achieved during repetitions will be measured using the Calf Raise App.
Change in heel raise work [baseline, 4 weeks, 16 weeks]
The subject will stand barefoot on a 10° incline board and perform heel raises at a rate of 30 Hz (2 seconds per repetition, pace provided by audible metronome), while keeping their knee straight. Subjects will be allowed to have 2 fingertips per hand at shoulder height against the wall for balance. Participants will stop when they are unable to perform any additional repetitions, or if they fail to maintain proper form. Total work (body weight x total distance) will be measured using the Calf Raise App.
Change in counter movement jump height [baseline, 4 weeks, 16 weeks]
Subjects will stand on a single leg with their hands behind their back, bend their knee as much as desired, and jump as high as possible from flat ground. Three trials will be performed. Jump height will be determined using the My Jump2 App and the highest jump height will be utilized in further analysis.
Change in drop counter movement jump height [baseline, 4 weeks, 16 weeks]
Subjects will stand on a single leg on top of an 8" plyometric box, with their hands behind their back. They will be asked to "fall" down to the floor and then immediately jump as high as possible from flat ground. Three trials will be performed. Jump height will be analyzed using the My Jump2 App and the highest jump height will be utilized in further analysis.
Change in VAS score during hopping [baseline, 4 weeks, 16 weeks]
Subjects will be asked to complete two 2 trials of 25 single leg hops at a natural cadence similar to jumping rope (~2 jumps/second). Subjects will be asked to rate their pain during the exercise using VAS (0-10).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Willing and able to provide informed consent for participation
Clinical diagnosis of Achilles tendinopathy
Pain disability index score of between 20 - 70 points (0-100 scale VISA-A)
Sonopalpation tenderness with tendon thickening and/or loss of fibrillary architecture.
Ability to read, speak, and understand English

Exclusion Criteria:

Any intervention (corticosteroids or other orthobiologic intervention as injection) to targeted tissue within the last 6 months.
Previous Achilles tendon surgery.
Known platelet abnormality or hematological disorder.
Presence of other conditions that might affect the functional scale of the indexed limb.
Unwillingness to be randomized.
Body Mass Index (BMI) greater than 30.
Occult tear in the indexed tendon.
Systemic inflammatory disease.
Use of fluoroquinolone in the past 6 months.
Subjects must not be pregnant or breastfeeding, or planning to become pregnant or breastfeed during the course of the trial
Chronic kidney disease (eGFR <60)
Diagnosis of diabetes mellitus or elevated HbA1c at screening (> 6.5)
Unable to take an oral medication in a non crushable pill form
Taking metformin presently or within the last 6 months
History of allergy to metformin
History of lactic acidosis or elevated lactate at screening (> 2.2)
Severe Hepatic dysfunction
Currently taking a diabetic medication such as sitagliptin, saxagliptin, linagliptin, alogliptin, sitagliptin with metformin
Currently taking a Carbonic anhydrase inhibitor such as topiramate, zonisamide, acetazolamide, dichlorphenamide, methazolamide
Currently taking cimetidine